Melatonin (N-acetyl-5-methoxytryptamine), which is a hormone synthesized and secreted principally in the pineal gland, increases in dark circumstances and decreases in light circumstances. Melatonin exerts suppressively on pigment cells and the female gonads, and acts as a synchronous factor of biological clock while taking part in transmittance of photoperiodic code. Therefore, melatonin is expected to be used for the therapy of diseases related with melatonin activity, such as reproduction and endocrinic disorders, sleep-awake rhythm disorders, jet-lag syndrome and various disorders related to aging, etc.
Recently, it has been reported that the production of melatonin melatonin could reset the body's aging clock (see Ann. N. Y. Acad. Sci., Vol. 719, pp. 456-460 (1994)). As previously reported, however, melatonin is easily metabolized by metabolic enzymes in vivo (see Clinical Examinations, Vol. 38, No. 11, pp. 282-284 (1994)). Therefore, it cannot be said that melatonin is suitable as a pharmaceutical substance.
Various melatonin agonists and antagonists such as those mentioned below are known. ##STR2## ##STR3##
Tricyclic or more poly-cyclic compounds with a cyclic ether moiety, such as those mentioned below, are known. ##STR4##
are disclosed in Tetrahedron Lett., Vol. 36, p. 7019 (1995). ##STR5##
are disclosed in J. Med. Chem., Vol. 35, p. 3625 (1992). ##STR6##
are disclosed in Tetrahedron, Vol. 48, p. 1039 (1992). ##STR7##
are disclosed in Tetrahedron Lett., Vol. 32, p. 3345 (1991). ##STR8##
is disclosed in Bioorg. Chem., Vol. 18, p. 291 (1990). ##STR9##
is disclosed in J. Electroanal. Chem. Interfacial Electrochem., Vol. 278, p. 249 (1990).
However, there is no report referring to the relationship between these compounds and melatonin receptors.
As tricyclic compounds with an affinity for melatonin receptor, known are compounds of: ##STR10##
wherein R.sup.1 represents a hydrogen atom, a halogen atom or a C.sub.1-6 alkyl group; R.sup.2 represents --CR.sup.3 R.sup.4 (CH.sub.2).sub.p NR.sup.5 COR.sup.6 (in which R.sup.3, R.sup.4 and R.sup.5 are the same or different and each represents a hydrogen atom or a C.sub.1-6 alkyl group, and R.sup.6 represents a C.sub.1-6 alkyl group or a C.sub.3-7 cycloalkyl group); n represents an integer of 2 to 4; and p represents an integer of from 1 to 4 (WO-A-9517405), and compounds of: ##STR11##
wherein R.sup.1 represents --CR.sup.3 R.sup.4 (CH.sub.2).sub.p NR.sup.5 COR.sup.6 (in which R.sup.3, R.sup.4 and R.sup.5 are the same or different and each represents a hydrogen atom or a C.sub.1-6 alkyl group, and R.sup.6 represents a C.sub.1-6 alkyl group or a C.sub.3-7 cycloalkyl group; R.sup.2 represents a hydrogen atom, a halogen atom, a C.sub.1-6 alkyl group, OR.sup.7 or CO.sub.2 R (in which R.sup.7 represents a hydrogen atom or a C.sub.1-6 alkyl group), provided that when q is 2, each of R.sup.2 are the same or different and each represents a hydrogen atom, a halogen atom, a C.sub.1-6 alkyl group, OR.sup.7 or CO.sub.2 R.sup.7 ; n represents an integer of 0 to 2; p represents an integer of 1 to 4; and q represents 1 or 2 (WO-A-9529173).
Melatonin agonists having different structures from that of melatonin and having an excellent binding affinity for melatonin receptor, excellent intracerebral mobility and excellent metabolical stability are expected to be more effective as a pharmaceutical remedy than melatonin.
At present, no compounds are known which are fully satisfactory with respect to their activity on melatonin receptor, and to their metabolical stability and the intracerebral mobility. Therefore, it is earnestly desired to develop compounds which are different from the above-mentioned known compounds in terms of their chemical structure, which have excellent agonistic or antagonistic activity towards melatonin receptor and which are therefore fully satisfactory for use in medicines such as pharmaceutical preparations.